Burden of sequelae and healthcare resource utilization in the first year of life in infants born with congenital cytomegalovirus (cCMV) infection in Germany: A retrospective statutory health insurance claims database analysis

Background Congenital cytomegalovirus (cCMV) infection can have a broad range of manifestations. This study aimed to assess cCMV-associated sequelae and healthcare resource utilization (HCRU) in infants during the first year of life in Germany. Methods A retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database was conducted. cCMV-associated sequelae and HCRU during the first year of life were assessed by matching (1:60) infants with at least one inpatient/outpatient cCMV diagnosis (ICD-10-GM: P35.1) ≤90 days after birth (cCMV90 cohort) and infants with at least one inpatient cCMV diagnosis plus specific sequelae ≤21 days after birth (cCMV21-S) to infants without cCMV or CMV (ICD-10-GM: B25) diagnosis (control group), respectively. Outcomes were analyzed during the first 365 days of life. Results Between 2014–2018, we identified 54 newborns for cCMV90 and 24 newborns for cCMV21-S cohort. Compared to the 3,240 and 1,440 controls, respectively, more cCMV90 infants (83.3% vs. 41.9%, p<0.01) presented with at least one sequela during the first year of life, including intrauterine growth retardation (42.6% vs. 5.3%, p<0.01), sensorineural hearing loss (SNHL) to deafness (38.9% vs. 2.2%, p<0.01), and motor development disorders (33.3% vs. 10.9%, p<0.01). Further, 13.0% of cCMV90 infants (vs. 2.3%, p<0.01) suffered from visual impairment. In cCMV21-S cohort, intrauterine growth retardation (79.2% vs. 6.0%, p<0.01), prematurity (54.2% vs. 7.3%, p<0.01), and motor development disorders (50.0% vs. 11.0%, p<0.01) were the most frequent sequelae. Infants in the cCMV90 and cCMV21-S cohort had, on average, 7.3 times and 9.5 times more hospitalizations and 2.0 times and 2.1 times more outpatient physician visits than their respective controls (p<0.01). Hospitalized infants with cCMV stayed, on average, significantly longer in hospital compared to their controls (cCMV90 cohort: 30.3 days vs. 9.0 days, p<0.01; cCMV21-S cohort: 46.5 days vs. 9.3 days, p<0.01). Conclusions cCMV-infection shows a considerable disease and healthcare burden during the first year of life. More than 80% of the identified newborns with cCMV suffered from at least one associated sequela during the first year of life, including long-term sequelae such as SNHL (40%) and visual impairment (13%). Additional steps for prevention of cCMV infection and associated sequelae as well as a comprehensive monitoring of disease burden are needed.


Introduction
Human cytomegalovirus (CMV) is a double stranded, enveloped DNA virus that belongs to the Herpesviridae family [1].Worldwide, CMV is estimated to have a seroprevalence of 83% in the general population [2].In Germany, the overall CMV seroprevalence in the adult population is found to be 56.7%[3].A recent meta-analysis estimated that globally 0.67% of individuals are congenitally infected with CMV [4].In Germany, estimates suggest that 0.2-0.5% of all living newborns are congenitally infected [5].
It is important to distinguish between postnatal and congenital CMV (cCMV) infection, as the long-term complications and treatment options differ considerably [6].While postnatal CMV infection has been considered to be of little clinical consequence in term infants [7], cCMV infection, on the other hand, can cause childhood disabilities, including neurological damage, growth retardation, sensorineural hearing loss, visual impairment and microcephaly [8][9][10][11].Compared to the incidence of other well-known congenital disabilities such as Down syndrome, neural tube defect, or fetal alcohol syndrome, cCMV appears to be more common, but public awareness seems to be lower [1,[12][13][14].
laws (Bundesdatenschutzgesetz). To facilitate the replication of results, anonymized data used for this study are stored on a secure drive at the Institute for Applied Health Research Berlin (InGef) GmbH.Access to the data used in this study can only be provided to external parties under the conditions of the cooperation contract of this research project and can be assessed upon request, after written approval at InGef GmbH (Tel.+49 (30) 21 23 36-471; info@ingef.de),if required.
Funding: MSD Sharp & Dohme GmbH funded the study and provided further support in the form of salaries [ML, AJS, RW, AL, MR] and expert honoraria for some of the authors [HB, RG, KH, PK, SM], which are described in detail in the "competing interests" section.The specific roles of these authors are articulated in the "author contributions" section.The funder approved the study design and manuscript for scientific integrity.The funder had no role in data collection and analysis as well as decision to publish.
Competing interests: ML, RW, AL, and MR are full-time employees of MSD Sharp & Dohme GmbH.AJS was a full-time employee of MSD Sharp & Dohme GmbH at the time the study was conducted.WW is a full-time employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.KMS and CJ are full-time employees of Xcenda GmbH, acting as contractors of MSD Sharp & Dohme GmbH for the execution of this study.WG received personal fees from Xcenda GmbH during the conduct of the study.RG, KH, PK, and SM received honoraria as scientific advisor from MSD Sharp & Dohme GmbH.HB received research grants (third-party funding), reimbursement of travel expenses, consulting fees or reimbursement of conference fees from the following companies related to the topic of 'cytomegalovirus infections': Biotest, MSD Sharp & Dohme GmbH, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Hoffmann-La Roche Ltd.This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Only limited real-world data exist on the disease burden of cCMV sequelae and the associated healthcare burden in infants with cCMV in Germany.Ru ¨tten et al. described up to 0.04% clinically relevant cCMV infections in all births in a retrospective study in Saxony-Anhalt, Germany [13].However, nationwide data is still lacking.
The present work covers one part of a large retrospective study that assessed the burden of cCMV in terms of sequelae, healthcare resource utilization (HCRU) and healthcare costs in infants during the first and second year of life from the perspective of the German statutory health insurance (SHI) [17].In this paper, we present the analysis of cCMV-associated sequelae and HCRU in infants with cCMV diagnoses compared to infants without cCMV in the first year of life (1-365 days).Additional data for cCMV-associated sequelae and HCRU in the second year of life (366-730 days) can be found in the see S1-S5 Tables.

Study design
Using a retrospective, controlled matched cohort design, we analyzed German SHI data from 2014-2019.Burden of cCMV was assessed in terms of cCMV-associated sequelae and HCRU in infants during their first year of life (1-365 days).

Database
In Germany, health insurance is mandatory, and approximately 88% of the German population, corresponding to about 73 million individuals, is insured under one of 110 public SHIs (as of 2018) [18].Since 1996, all individuals insured by the SHI are free to choose their health insurance fund.All public SHIs offer the same comprehensive benefits package, as the contents to be reimbursed are defined in Social Law.
We utilized the Institute for Applied Health Research Berlin (InGef) database with claims data from about 60 different SHIs covering approximately 8 million lives insured in one of the contributing SHIs (mainly company or guild health insurances).The InGef database has a well-distributed geographic representation of the German population and good external validity in terms of morbidity, mortality, and drug use [19,20].Newborns identified in the InGef database (females 48.6%, males 51.4%) represented 7.8% (n = 298,112) of live births in Germany between 2014-2018 with a similar sex distribution as the German population (females 48.7%, males 51.3%) [21].The database includes information on all different healthcare sectors such as the inpatient, outpatient, and the pharmacy sector.Data generation occurs routinely during health service provision or during the reimbursement process and reflects the actual utilization of health services from the payers' perspective across various providers and sectors.

Ethics approval and consent to participate
Claims data from the participating SHIs are joined in a specialized trust center, anonymized, and transferred to InGef before the data are made available for research.In accordance with the "GPS-Good Practice in Secondary Data Analysis" (Guideline 1: Ethics) [22], the analysis of claims data from the SHI is permitted and does not require the approval of an ethics committee.

Study population
All newborns available in the InGef database from 2014-2018 were considered for this study.Newborns needed to be continuously observable for at least 365 days of life, except for infants who deceased.Infants with pre-defined diagnoses (leukemia, human immunodeficiency virus (HIV), solid organ transplant, or stem cell transplant) during the first 365 days of life were excluded from the study population (see S6 Table ).
Two cCMV cohorts and one control group were defined: ■ Study cohorts: • cCMV-cohort 1 (cCMV 90 ): all infants with a documented ICD-10-GM (International Classification of Diseases, 10 th Revision, German Modification) diagnosis for cCMV (P35.• all infants without a documented ICD-10-GM diagnosis for cCMV (P35.1) and CMV (B25) at any time during their individual observation period in the database A more detailed description of selection criteria including information on the German claims data coding system can be found in the S1 File.
A direct 1:60 matching without replacement based on gender, year-specific quarter of birth, and observability of the newborns was performed.Cases needed to be continuously observable for at least 365 days of life except for infants who died during the follow-up.If cases deceased during follow-up, these infants were analyzed until death.Since controls needed to be continuously observable for at least as long as their matched cCMV cases, controls were censored at date of death of the matched case.No controls that deceased during the follow-up period were selected for the matching.No cases were lost during the matching procedure.The matching and data analysis were conducted using "R 3.5.0"software.

Outcomes
Pre-defined sequelae associated with cCMV (based on clinical expertise and published literature [23]) were identified by ICD-10-GM codes in the outpatient (verified diagnoses) and inpatient (primary or secondary diagnoses) setting (see S7 Table ) and reported as the number and percentage of infants with at least one respective comorbid diagnosis related to cCMV observed during the first year of life.
HCRU was analyzed regarding inpatient and outpatient care.For inpatient care we analyzed proportions of infants with hospitalizations, frequency of hospitalizations (in all matched infants), length of stay (in matched infants with hospitalizations), and reasons for hospitalizations defined as primary inpatient diagnosis (3-digit ICD-10-GM code).
For outpatient care we analyzed frequency of physician visits, proportions of infants with and frequency of physical and occupational therapy, and proportions of infants with outpatient pharmaceutical prescriptions identified by 7-digit Anatomical Therapeutic Chemical (ATC) classification codes.Reasons for outpatient visits were summarized based on verified 3-digit ICD-10-GM codes.

Statistical analysis
Descriptive analyses were performed for patient demographics, cCMV-associated sequelae, and HCRU in terms of mean values, medians, ranges, and standard deviations of continuous variables of interest and frequency distributions for categorical variables.For continuous variables, mean differences with respective 95% confidence intervals were additionally calculated.Statistical significance of observed numerical differences in outcomes between cohorts was assessed using Mantel-Haenszel matched-pairs test for dichotomous variables and Wilcoxon rank-sum test for continuous variables.P-value <0.05 was considered as statistically significant.

Healthcare resource use
Hospitalizations.Almost all infants in the cCMV 90 cohort (98.1%) were at least once hospitalized during their first year of life (Table 2).The two most frequent 3-digit ICD-10-GM primary diagnoses (highest percentage of infants with at least one code) in the cCMV 90 cohort with significant differences to their controls were disorders of newborn related to short gestation and low birth weight (P07, 29.6% vs. 4.7%, p<0.01), and conductive and sensorineural hearing loss (H90, 16.7% vs. 0.7%, p<0.01).Additionally, 70.4% of infants in the cCMV 90 cohort were hospitalized at least once for congenital viral diseases, incl.cCMV (P35) and 20.4% of infants for cytomegaloviral disease (B25) (see S9 Table ).
All infants in the cCMV 21-S cohort presented with a cCMV-related hospitalization (ICD-10-GM code P35.1 as primary or secondary diagnoses) during the first 21 days of life as this was part of the inclusion criteria for this cohort (Table 2).The two most common 3-digit ICD-10-GM primary diagnoses in the cCMV 21-S cohort with significant differences to their controls were for disorders related to prematurity and low birthweight (P07, 58.3% vs. 5.4%, p<0.01) and conductive and sensorineural hearing loss (H90, 25.0% vs. 0.6%, p<0.01).Additionally, 58.3% of all infants in the cCMV 21-S cohort were hospitalized at least once for congenital viral diseases, incl.cCMV (P35), and 37.5% of infants for cytomegaloviral disease (B25) (see S9 Table ).
Outpatient care.Infants in both cCMV cohorts had more outpatient physician visits compared to their respective controls during the first year of life.On average, infants in cCMV 90 cohort had 2.0 times more outpatient physician visits (27.7 vs. 14.1 visits, p<0.01) and infants in the cCMV 21-S cohort 2.1 times more visits (30.3 vs. 14.1 visits, p<0.01) than the control group (Table 2).The most frequently documented outpatient ICD-10-GM diagnoses in both cCMV cohorts and the control group did not differ significantly, as these were related to encounters for general examination or vaccination.

Discussion
During the first year of life, more than 80% of infants with a cCMV diagnosis in our study presented with at least one cCMV-associated sequela, with intrauterine growth retardation, sensorineural hearing loss to deafness, and motor development disorders being the most frequently observed diagnoses.Further, infants with cCMV were statistically more frequently hospitalized and had more outpatient physician visits compared to infants without cCMV.Nevertheless, there is limited awareness and knowledge of cCMV infection in everyday clinical practice [24][25][26], which may lead to an underestimation of cCMV burden in Germany.Even when typical cCMV symptoms are present, cCMV infection may not always be considered by physicians as a potential cause and therefore no further diagnostics for cCMV may be performed [27].Based on the results of our study, intrauterine growth retardation was the most frequent sequela in both the cCMV 90 and cCMV 21-S cohort (42.6% and 79.2%, respectively), which may provide an important clue to cCMV infection.It may be reasonable to suggest testing for cCMV infection in infants with unexplained intrauterine growth retardation at birth or prematurity [28].Targeted CMV testing among newborns who failed newborn hearing screening, has been explored by different study groups [29,30].The study by Fowler et al. [29] evaluated a group of newborns specifically screened for CMV, who underwent newborn hearing screening in the follow-up.They found that among 443 newborns with positive CMV test result, 20 (4.5%) newborns with sensorineural hearing loss could be identified via newborn hearing screening.Considering only the 35 CMV-positive infants with sensorineural hearing loss, 20 (57%) of newborns with CMV-related sensorineural hearing loss were identified via newborn hearing screening.Although newborn hearing screening may not be able to identify all newborns with CMV-related sensorineural hearing and by the time hearing loss is confirmed by diagnostic audiologic evaluation it may be too late to confirm cCMV, targeted CMV testing in those infants with unexplained hearing loss might be a supportive measure to identify CMV-related impairments in infants.Also, less common diagnoses such as visual impairment may be an important indication for cCMV infection.For instance, visual impairment was diagnosed in about 13% of the identified cCMV infants.Even though this was not amongst the most frequently identified sequelae, it may comprise a substantial clinical burden to the infants in the long-term as many of the affected infants require ongoing care and special therapeutic and educational services, which lead to considerable healthcare burden [31].In general, there is a necessity for more awareness of cCMV infection in newborns and associated complications.Generally, our results are in line with the sparse information currently available in the literature.In our study, sensorineural hearing loss was diagnosed in around 39% of infants with cCMV during the first year of life, which is within the range of findings from other studies (32%-41% in symptomatic cCMV infants) [32].Our results suggest that infants diagnosed with cCMV are likely to suffer from more than one sequela during the first year of life, which has also been reported by Modrow and colleagues [23].
However, not all infants with a cCMV diagnosis showed a record for any of the pre-defined cCMV-specific sequelae and not all pre-defined sequelae reported in the literature like optic atrophy, chorioretinitis, pneumonia, and abnormal findings in cerebrospinal fluid, were identified in our cCMV cohorts [23].Nevertheless, it may be reasonable to assume that all infants with a confirmed cCMV diagnosis in our dataset might have been symptomatic in one way or another.We hypothesize that all infants must have been detected and diagnosed after targeted investigation, possibly triggered by signs or symptoms in the infant's development suspicious for cCMV infection, as to date no national screening program for cCMV exists in Germany.There are two possible explanations for the lack of recorded symptoms in these infants: 1) Frequently, only ICD-10-GM codes that are relevant for reimbursement purposes are coded by the physician and it might be possible that physicians did not record all symptoms (ICD-10-GM codes), as they might have not been relevant for reimbursement; 2) we assessed the occurrence of pre-defined ICD-10-GM codes based on clinical expertise and published literature [23], the list of relevant diagnoses, however, could be incomplete.In both cases the burden of cCMV sequelae reported in this study might underestimate the true clinical burden.
Depending on the definition of infants with cCMV used in this study, the reported frequency of sequelae and differences to the control group vary by comparison.The decision to use two alternative definitions for cCMV was based on the uncertainty associated with the attempt to retrospectively distinguish infants with cCMV infection from infants with postnatal CMV infection solely based on claims data information [6].
Moreover, this study focused on the first year of life, even though some sequelae will affect the infants for the rest of their life and some sequelae of previously asymptomatic infants might be detected later in life, such as sensorineural hearing loss and cognitive impairment [32].Delayed onset hearing loss, for instance, has been reported to occur in about 7-10% of initially asymptomatic infants at a median age of 44 months [33].Due to potential late-onset of hearing impairments, it is possible that these may be missed by universal hearing screening [28,34] and even if detected, the association between hearing loss and cCMV infection may no longer be identifiable at this point.Even though a timely diagnosis of cCMV infection in symptomatic as well as asymptomatic newborns is crucial for early interventions with improved chances of reducing the risk of severe and permanent disabilities [23,25], to date, national newborn screening for cCMV is not established in Germany.
The resource use associated with management and treatment of cCMV infection and associated sequelae, especially in the year of life, was barely assessed so far.In a retrospective cohort study from Israel, infants with cCMV were nearly twice as likely to have a hospital admission compared to their controls (8.5% cases vs 4.5% control; p<0.001) [35].A retrospective administrative health insurance claims database analysis from the US compared HCRU and costs between infants with cCMV diagnosis at birth and during the first year of life versus matched infants without diagnosed cCMV [36].The study found that around 32% of the cCMV infants had at least one all-cause hospitalization during the 12-month follow-up period.Almost all infants with cCMV in our study had been hospitalized at least once during the first year of life.This remarkably higher proportion can be explained by the fact that birth itself constitutes one important reason for hospitalization in the first year of life.Even though both studies included the day of birth in the follow-up period, in the US, birth-related claims may have been included on a mother's insurance policy [36], whereas in Germany each newborn, theoretically, has its own insurance coverage beginning with the birthday.
Additionally, in our study we observed twice as many outpatient physician visits in the cCMV cohorts compared to their controls.One factor contributing to these excess outpatients visits might be follow-up visitis for check-up and associated pharmaceutical treatments such as valganciclovir or ganciclovir.Currently, there are still no approved drugs for cCMV treatment in infants [31].Newborns with symptomatic cCMV infection may receive (currently off-label use) antiviral therapy with valganciclovir or ganciclovir depending on disease severity and presence of symptoms [9,23,33,37].The observed outpatient prescriptions of valganciclovir in the cCMV 90 and the cCMV 21-S cohorts (35.2% and 50.0%, respectively) indicate that there is need for the treatment of cCMV to reduce viral burden and the risk of severe disabilities in these infants.It should be considered that the actual number of infants receiving antiviral therapy might be underestimated in our study as due to the nature of this database, most pharmaceuticals dispensed in the inpatient setting are covered as lump sums by the German Diagnosis Related Group (G-DRG) reimbursement system and are therefore not separately identifiable in German claims data records.
Additional limitations of our study are associated with difficulties in the retrospective identification of infants with cCMV (e.g., dried blood spots are destroyed in Germany 90 days after birth) [6,38], as well as special challenges concerning the identification of cCMV in electronic health records [39,40].Claims data are primarily collected for reimbursement purposes, i.e., the database includes only information on infants who have seen a physician and caused reimbursement for the health insurance.Moreover, clinical or laboratory results are not available in the database.Therefore, differentiation between virologically confirmed diagnoses and other (clinical) reasons for entry of cCMV records is not available.Consequently, the classification of infants in the cCMV cohorts depends to some extent on the ICD coding behavior of physicians, which, as common for secondary data analyses, was beyond our control.Data are anonymized for data protection reasons, so validation of diagnoses against medical charts is not possible.At present, there are also no additional validated tools available to specifically identify infants with cCMV in German claims databases.Therefore, we established a detailed identification process for infants with cCMV.In the case definition, no specific symptoms for the cCMV 90 cohort were required.However, as there is no universal newborn screening for cCMV in Germany, we assume that infants in the cCMV 90 cohort must have been detected and diagnosed after targeted investigation, possibly triggered by signs or symptoms in their development, so that they were symptomatic to some extent, i.e., asymptomatic cCMV or misdiagnosed symptomatic infants are likely not covered by our study population.In this context, the actual burden of cCMV in Germany may be underestimated, since undiagnosed patients as well as services that are not reimbursed by the SHI (e.g.certain individual health services) have not been captured in the database.Also infants in the control group may not have been strictly investigated for cCMV typical sequelae resulting in an underestimation of those diagnoses in the control group.bias might have induced an increased difference between cases and controls.
Considering the presumably underestimated frequencies of sequelae from this study, it is essential to understand the actual burden of sequelae and HCRU in newborns with cCMV infection.A systematic collection of information (by physicians and laboratories) would offer the opportunity to produce reliable numbers on the actual burden of cCMV and associated sequelae in newborns in Germany and finally, to diagnose and manage potential cCMV infections as early as possible.

Conclusion
In Germany, the burden of sequelae in the first year of life in children diagnosed with cCMV is high, with significant differences compared to children without cCMV diagnosis.More than 80% of all identified infants with cCMV diagnosed during the first 90 days of life suffer from at least one sequela during the first year of life, which include also long-term disabilities such as sensorineural hearing loss to deafness and visual impairment.The potential disease and healthcare burden in infants with cCMV diagnoses calls for preventative steps against cCMV infection and a comprehensive monitoring of cCMV and its sequelae in Germany.

Fig 1 .
Fig 1. Patient selection process-First year of life (1-365 days).InGef, Institute for Applied Health Research Berlin; cCMV, congenital cytomegalovirus; cCMV 90 , infants with cCMV diagnosis during the first 90 days of life; cCMV 21-S , infants with inpatient cCMV diagnosis and symptoms during the first 21 days of life; Controls, infants with no cCMV or CMV diagnosis in the observation period; DoL, days of life.https://doi.org/10.1371/journal.pone.0293869.g001

Table 3 . Proportions of infants with at least one respective outpatient prescription a during 1-365 days of life.
P-value <0.05 was considered as statistically significant (Mantel-Haenszel matched-pairs test).cCMV, congenital cytomegalovirus; cCMV 90 , infants with cCMV diagnosis during the first 90 days of life; cCMV 21-S , infants with inpatient cCMV diagnosis and symptoms during the first 21 days of life; Controls, infants with no cCMV or CMV diagnosis in the observation period; ATC, Anatomical Therapeutic Chemical.
a Only substances which were prescribed for at least 5 infants in cCMV 90 are displayed.b

Table 4 . Physical and occupational therapy prescriptions during the first 1-365 days of life.
Due to missing data, results for physical and occupational therapy prescriptions are based on n = 44 infants in cCMV 90 cohort and n = 21 infants in cCMV 21-S cohort with valid data for physical and/or occupational therapies.cCMV, congenital cytomegalovirus; cCMV 90 , infants with cCMV diagnosis during the first 90 days of life; cCMV 21-S , infants with inpatient cCMV diagnosis and symptoms during the first 21 days of life; Controls, infants with no cCMV or CMV diagnosis in the observation period; CI, 95% confidence interval; SD, standard deviation; Min, minimum; Q1, 25 th percentile; Q3, 75 th percentile; Max, maximum; No = number.